Stilbenes Inhibit Androgen Receptor Expression in 22Rv1 Castrate-resistant Prostate Cancer Cells


Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced castrate-resistant PCa (CRPC), where the AR can have ligand-independent activity. Identification of naturally occurring substances that can inhibit AR expression holds promise for PCa chemoprevention and therapy. Earlier research demonstrated that resveratrol (Res) inhibited androgenpromoted growth, AR expression, and transactivation in androgen-responsive non-metastatic LNCaP PCa cells. In the current study, the effects of Res and three natural analogs [trimethoxyresveratrol (3M-Res), pterostilbene (Pter), and piceatannol (Pic)] were investigated for effects on the growth of 22Rv1 castrate-resistant cells that express full-length (AR114/110) and truncated form (AR80) of AR. Although all the stilbenes tested inhibited the proliferation of 22Rv1 cells in a dose-dependent manner, 3M-Res was the most potent inhibitor. While AR114/110 responded to the syn-thetic androgen agonist methyltrienolone (R1881) as well as to antiandrogen flutamide, AR80, which lacks a ligand-binding domain, did not respond to R1881, but was inhibited by flutamide. Interestingly, Res, Pter, and Pic, but not 3M-Res, similar to flutamide, inhibited both AR114/110 and AR80 with the effect on AR80 being more prominent with the use of high concentrations of stilbenes. Collectively, the data indicate that both AR-independent (3M-Res) and possibly AR-dependent (Res, Pter, and Pic) mechanisms of cell growth inhibition occurs via these stilbenes. These findings provide evidence for plant-derived stilbenes as attractive and promising pharmacologically safe compounds to be used for diminishing progression and curb worsening of CRPC.